A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse

• DOI: 10.1073/pnas.0709846104
• Publication Date: 2007-11-29T01:45:29Z
• Authors: Christian Grimm; Math P. Cuajungco; Alexander F. J. v...; Michael Schnee; Simone Jörs; Corné J. Kros; Anthony J. Ricci; Stefan Heller
• Keywords: 0301 basic medicine; Proline; Molecular Sequence Data; TRPM Cation Channels; Apoptosis; Protein Structure, Secondary; Cell Line; Protein Structure, Tertiary; Mice; 03 medical and health sciences; Transient Receptor Potential Channels; Amino Acid Substitution; Animals; Amino Acid Sequence; Hearing Loss

Homozygote varitint-waddler ( Va ) mice, expressing a mutant isoform (A419P) of TRPML3 (mucolipin 3), are profoundly deaf and display vestibular and pigmentation deficiencies, sterility, and perinatal lethality. Here we show that the varitint-waddler isoform of TRPML3 carrying an A419P mutation represents a constitutively active cation channel that can also be identified in native varitint-waddler hair cells as a distinct inwardly rectifying current. We hypothesize that the constitutive activation of TRPML3 occurs as a result of a helix-breaking proline substitution in transmembrane-spanning domain 5 (TM5). A proline substitution scan demonstrated that the inner third of TRPML3's TM5 is highly susceptible to proline-based kinks. Proline substitutions in TM5 of other TRP channels revealed that TRPML1, TRPML2, TRPV5, and TRPV6 display a similar susceptibility at comparable positions, whereas other TRP channels were not affected. We conclude that the molecular basis for deafness in the varitint-waddler mouse is the result of hair cell death caused by constitutive TRPML3 activity. To our knowledge, our study provides the first direct mechanistic link of a mutation in a TRP ion channel with mammalian hearing loss.